Functional Analysis of Genes and Genomic Variants in Animal Models
动物模型中基因和基因组变异的功能分析
基本信息
- 批准号:9124899
- 负责人:
- 金额:$ 53.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-04-01 至
- 项目状态:未结题
- 来源:
- 关键词:AllelesAnatomyAnimal ModelBenignBioinformaticsBiologicalBiological ModelsBiological ProcessCRISPR/Cas technologyCandidate Disease GeneClinicalCodon NucleotidesCommunitiesDevelopmentDiseaseExpert SystemsFunctional disorderGene StructureGene TargetingGenesGenomeGenomicsGenotypeGoalsHumanHuman GenomeImageryMediatingMethodsModelingMusMutagenesisMutationOrthologous GeneOutcomePathogenicityPatientsPhenotypePoint MutationReporterResearchResearch Project GrantsSystems AnalysisTechnologyTestingTransgenic OrganismsValidationVariantZebrafishabstractingbasebiological systemsbody systemclinical phenotypecohortdesignexomegene discoverygene functiongenetic variantgenome analysisgenome editinggenome wide association studyhigh throughput analysishigh throughput screeninghuman genomicsin vitro Modelin vivoinnovationinsightinterestknock-downloss of functionmutantnovelspatiotemporal
项目摘要
PROJECT 2 ABSTRACT/RESEARCH SUMMARY.
Project 1 of DGAP takes advantage of a robust clinical referral network and innovations in genome analysis
approaches to identify disease associated genes-of-interest using BCAs. Akin to other human genomics
research projects (e.g., GWAS, WES/WGS), we are generating a rapidly expanding candidate gene list that is
outpacing the functional analysis to validate the causal relationship and understand the underlying
pathophysiology. Use of an animal model to disrupt the human ortholog and recapitulate the clinical phenotype
remains the best functional evidence for gene function and pathogenicity of gene variants. Major advances in
gene targeting methods now make it possible to functionally annotate human candidate genes in a higher
throughput and precisely targeted fashion. Further, the biologic advantages and wealth of transgenic reporters
allows for rapid phenotypic analysis from direct visualization of the biological process of interest. The goal of
Project 2 is to use the convergence of advanced gene editing state-of-the-art biological system
analyses and convergent bioinformatics to establish rapidly functional evidence for genes-of-interest.
We have designed Project 2 to provide ready-to-use deliverables to the scientific community. Aim 1 utilizes
high-throughput in vivo spatiotemporal expression analysis and morpholino-mediated gene knockdown to
rapidly analyze the function of candidate genes (approximately 30 per year) discovered at the BCA
breakpoints. Aim 2 applies high-throughput targeted mutagenesis using CRISPR/Cas9 approach to generate
loss-of-function zebrafish models (approximately 10-15 genes per year) to provide functional evidence for
consequences of DGAP gene disruptions in the appropriate biologic context. All organ systems will be
examined via rapid phenotype assessment strategy, supported by a consultant team of zebrafish biologists as
needed, while genes with potential function in neuro-development will be forwarded for analysis in Project 3.
Aim 3 takes advantage of the animal models to carry out high-throughput analysis of human gene variants to
determine pathogenicity of the mutation (approximately 10-12 variants per year). Project 2 will make a
significant contribution to functional gene annotation discovered through the DGAP pipeline, innovate
strategies to analyze human genome variants, and generate deliverables to the scientific community to
catalyze biological explorations across organ systems.
项目2摘要/研究总结。
DGAP的项目1利用了强大的临床转诊网络和基因组分析的创新
使用BCA鉴定疾病相关的感兴趣基因的方法。类似于其他人类基因组学
研究项目(例如,GWAS,WES/WGS),我们正在生成一个快速扩展的候选基因列表,
超越功能分析,以验证因果关系,并了解潜在的
病理生理学使用动物模型破坏人类直系同源物并重现临床表型
仍然是基因功能和基因变异致病性的最佳功能证据。重大进展
基因靶向方法现在使得有可能在更高的水平上对人类候选基因进行功能注释。
吞吐量和精确的针对性方式。此外,转基因报告基因的生物学优势和丰富性
允许从感兴趣的生物过程的直接可视化进行快速表型分析。的目标
项目二是使用融合先进基因编辑技术的最先进生物系统
分析和聚合生物信息学,以快速建立感兴趣基因的功能证据。
我们设计了项目2,为科学界提供现成的可交付成果。目标1利用
高通量体内时空表达分析和吗啉代介导基因敲除,
快速分析在BCA发现的候选基因(每年约30个)的功能
断点。目的2应用使用CRISPR/Cas9方法的高通量靶向诱变来产生
功能丧失的斑马鱼模型(每年大约10 - 15个基因),为以下方面提供功能证据:
在适当的生物学背景下DGAP基因破坏的后果。所有的器官系统都将
通过快速表型评估策略进行检查,由斑马鱼生物学家顾问团队提供支持,
需要,而在神经发育中具有潜在功能的基因将在项目3中进行分析。
目的3利用动物模型进行人类基因变异的高通量分析,
确定突变的致病性(每年约10 - 12种变异)。项目2将使
对通过DGAP管道发现的功能基因注释做出了重大贡献,
分析人类基因组变异的战略,并为科学界提供可交付成果,
催化器官系统的生物探索。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eric Chien-Wei Liao其他文献
Eric Chien-Wei Liao的其他文献
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转让 5R01DE027983 - IRF6 靶基因在口面裂发病机制中的基因组和功能分析
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Transfer 5R01DE027983 - Genomic and Functional Analysis of IRF6 Target Genes in Orofacial Cleft Pathogenesis
转让 5R01DE027983 - IRF6 靶基因在口面裂发病机制中的基因组和功能分析
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Genomic and Functional Analysis of IRF6 Target Genes in Orofacial Cleft Pathogenesis
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